Hydroxy- and oxo-substituted α-benzylidenylcycloalkanes having the formula: ##STR1## Z1, Z2 and Z3 each denotes a methoxy group or Z1 or Z2 and Z3 together denote a methylenedioxy group, and Z3 is a hydrogen atom or chlorine atom, one of the symbols R1 and R2 denotes a hydrogen atom and the other denotes a hydroxyl group or, together the two denote an oxygen atom; R3 denotes a hydrogen atom or a methyl group; R4 denotes a hydrogen atom, a methyl group or an aminomethyl group, the amino group being a dimethylamino, diethylamino, morpholino, 4-methyl-piperazino or piperidino radical; or R3 and R4 together denote a piperonylidene group; R5 denotes a hydrogen atom or a methyl group, and A forms, with the carbon atoms to which it is attached, a cyclopentane, cyclohexane, indane, tetrahydronaphthalene, perhydronaphthalene or piperidine structure and the pharmaceutically acceptable addition salts of the compounds containing an amino group.
The compounds have pharmacological activity on the central nervous system.
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2. 2-piperonylidene-6-methylcyclohexanol.
1. 2-piperonylidene-6-morpholinomethylcyclohexanol.
3. A method for treating anxious or depressive syndromes in a patient which comprises administering to said patient a pharmaceutical compound of
4. A pharmaceutical composition for treatinan axious or depressive syndrome which contains a compound of
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The objects of the present invention are α-benzylidenecycloalkanones and the corresponding alcohols, their preparation, and their use as medicaments.
The compounds of the invention have the formula ##STR2## in which Z1, Z2 and Z3 each denotes a methoxy group or Z1 and Z2 together denote a methylenedioxy group, and Z3 is a hydrogen atom or chlorine atom,
one of the symbols R1 and R2 denotes a hydrogen atom and the other denotes a hydroxyl group or, together, the two denote an oxygen atom,
R3 denotes a hydrogen atom or a methyl group,
R4 denotes a hydrogen atom, a methyl group or an aminomethyl group, the amino group being a dimethylamino, diethylamino, morpholino, 4-methylpiperazino or piperidino radical; or R3 and R4 together denote a piperonylidene group,
R5 denotes a hydrogen atom or a methyl group, and
A forms, with the carbon atoms to which it is attached, a cyclopentane, cyclohexane, indane, tetrahydronaphthalene, perhydronaphthalene or piperidine structure,
as well as the pharmaceutically acceptable addition salts of the compounds containing an amino group.
The invention more particularly concerns the compounds of the formula (I) in which A forms together with the carbon atoms to which it is attached a cyclohexane group, that is to say the compounds of the formula ##STR3## in which the different symbols have the same meaning as in formula (I).
The compounds may be prepared by condensing aldehydes of the formula ##STR4## with a ketone of the formula ##STR5## in which formulae the symbols Z1, Z2, Z3, R3, R4, A and R5 have the meanings given above, in an aqueous or alcoholic medium and in equimolecular amounts.
A α-ethylenic ketone of the formula ##STR6## is thus obtained.
In order to obtain the corresponding α-ethylenic alcohol of the formula ##STR7## the keytone (Ia) is reduced, for example by means of potassium or sodium borohydride in an alcoholic medium. In these formulae, the symbols Z1, Z2, Z3, R3, R4, A and R5 have the same meanings as in the formula (I).
In order to prepare the compounds of the general formula (I) containing a R4 group=aminomethyl, the following method may advantageously be employed. The ketone of the formula (Ia) in which R3 =R4 =H is prepared, and aminomethylation is carried out to introduce the R4 group by means of the amine corresponding to R4 and formaldehyde.
The following examples illustrate the preparation of the compounds of the invention.
PAC 2-(3,4-methylenedioxybenzylidene)-6-methylcyclohexanone or 2-piperonylidene-6-methylcyclohexanone (Code No. 993)15 g (0.1 mole) of piperonal, 11.2 g (0.1 mole) of 2-methylcyclohexanone, and 2 sodium hydroxide pellets in 100 cm3 of ethanol are boiled under reflux for 6 hours. The ethanol is distilled off and the product is taken up in water. The product is extracted with chloroform and the oil obtained is distilled (B.P.13 mm =228°). The product is recrystallised from ethanol. M.P.=78°; yield 57%.
PAC 2-(3,4-methylenedioxybenzylidene)-6-methylcyclohexanol or 2-piperonylidene-6-methylcyclohexanol (Code No. 1040).0.1 mole of the ketone (993) obtained according to Example 1 is dissolved in 300 cm3 of methanol and an aqueous solution of KBH4 is added dropwise. The product obtained is extracted with chloroform and recrystallised from petroleum ether. M.P.=62°; yield 75%.
PAC 2-(piperonylidene)-6-morpholinomethylcyclohexanone and its hydrochloride (Code No. 1325)23 g of 2-(piperonylidene)-cyclohexanone (0.1 mole), 3 g of paraformaldehyde (0.1 mole) and 12.5 g of morpholine hydrochloride (0.1 mole) in 75 cm3 of absolute ethanol adjusted to a pH-value of 3, are boiled under reflux for 8 hours.
The hydrochloride formed is filtered and recrystallised from nitroethane. M.P.=210°; yield 50%.
A part of the hydrochloride is decomposed with sodium carbonate. The base is recrystallised from ethanol. M.P.=180°.
PAC 2-(piperonylidene)-6-morpholinomethylcyclohexanol (Code No. 1347)The ketone prepared according to Example 3 is used as starting material and the same technique is employed as in Example 2, except that extraction is carried out with ether and the product is recrystallised from ethanol. M.P.=124°, yield 67%.
The compounds of the preceding examples as well as other compounds prepared in a similar manner are given in the following Table I. The abbreviations used are as follows
edp=petroleum ether
DMF=dimethylformamide
cyclo=cyclohexane.
| TABLE I |
| __________________________________________________________________________ |
| Code No. |
| of cor- |
| M.P. (°C.) |
| M.P. (°C.) |
| respond- |
| base hydrochloride |
| Code |
| Formula ing (recrystallisation sol- |
| No. (ketones) alcohol |
| vent) |
| __________________________________________________________________________ |
| 993 |
| ##STR8## 1040 78 (ethanol) |
| 994 |
| ##STR9## 1446 120 (ethanol) |
| 1386 |
| ##STR10## 1387 100 (ethanol) |
| 1292 |
| ##STR11## 1322 180 (acetone) |
| 1293 |
| ##STR12## 1388 133 (ethanol) |
| 1059 |
| ##STR13## 168 (nitromethane) |
| 1323 |
| ##STR14## 1324 220 (DMF) |
| 1325 |
| ##STR15## 1347 180 (ethanol) |
| 210 (nitroethane) |
| 1348 |
| ##STR16## 1349 52 (edp) 202 |
| 1350 |
| ##STR17## 1351 116 (ethanol) |
| 185 |
| 1352 |
| ##STR18## 1353 132 (ethanol) |
| 202 (2HCl) |
| l354 |
| ##STR19## 1355 114 (methanol) |
| 1274 |
| ##STR20## 1275 108 (ethanol) |
| 1266 |
| ##STR21## 1267 67 (cyclo- hexane) |
| 1268 |
| ##STR22## 1269 95 (ethanol) |
| 1270 |
| ##STR23## 1271 62 (edp) |
| Code No. |
| of cor- |
| respond- |
| M. P. (°C.) |
| M. P. (°C.) |
| Code |
| Formula ing base hydrochloride |
| No. (alcohols) ketones |
| (recrystallisation |
| __________________________________________________________________________ |
| solvent |
| 1040 |
| ##STR24## 993 62 (edp) |
| 1446 |
| ##STR25## 994 oil nD25 = 1,5675 |
| 1387 |
| ##STR26## 1386 52 (edp 60 cyclo 40) |
| 1322 |
| ##STR27## 1292 122 (isopro- panol) |
| 1388 |
| ##STR28## 1293 146 (ethanol) |
| 1324 |
| ##STR29## 1323 180 (ethanol 50 water 50) |
| 1347 |
| ##STR30## 1325 194 236 (ethanol) |
| 1349 |
| ##STR31## 1348 oil η=1,5535 |
| 185 (ethanol) |
| 1351 |
| ##STR32## 1350 95 252 (ethanol) |
| 1353 |
| ##STR33## 1352 128 250 |
| (2HCl) (ethanol) |
| 1355 |
| ##STR34## 1354 120 |
| 1275 |
| ##STR35## 1274 95 (pentane) |
| 1267 |
| ##STR36## 1266 oil nD25 = 1,5460 |
| 1269 |
| ##STR37## 1268 oil nD25 = 1,5518 |
| 1271 |
| ##STR38## 1270 oil nD25 |
| __________________________________________________________________________ |
| = 1,5398 |
The compounds of the invention have been tested pharmacologically.
The LD50 of the products was determined in mice by the intraperitoneal route according to the "Log-Probits" method of Miller and Tainter (Proc. Soc. Exptl. Biol. Med. 1944; 57, 261-264).
This was investigated by observing the behaviour of the animal by studying the modification in hexobarbital-induced narcosis and antagonism vis-a-vis reserpine.
Mice, each weighing about 20 g, received intraperitoneally the product being investigated. Half an hour later sodium hexobarbital was injected by the same route at a dosage of 70 mg/kg.
The animals were placed on a hot plate maintained at a constant temperature of 27°C Sleep is considered to have occurred as soon as a mouse, placed in the dorsal decubitus position, is incapable of turning over onto its paws.
The narcosis potentialisation is evaluated from the percentage increase in sleep time induced by hexobarbital (T).
(Chen G., and Bohner B., (1961) J. pharmacol Exptl. Therap. 131, 179).
Reserpine when administered intraperitoneally to mice in a dosage of 5 mg/kg causes the eyelids to close more or less completely in the majority of animals. The administration of certain products will inhibit the blepharospasm produced by reserpine.
Swiss male mice are distributed into groups of 10 mice, and each experiment includes at least 3 groups:
a control group that receives only the solvent and reserpine
a group treated with a reference product (we chose Imipramine)
a treated group that receives the product being tested.
The products under investigation are administered intraperitoneally at 30 minutes or 2 hours before intraperitoneal injection of reserpine in a dosage of 5 mg/kg, so as to study their activity as a function of time.
The degree of ptosis for each eye and each animal is observed every 30 minutes for 4 to 5 hours, using RUBIN's score method. The activity of the product is determined by comparison with the result obtained with the treated control group. The inhibition of blepharospasm is recorded from 0 to +++.
The results obtained in the various tests are given in the following Table II.
| TABLE II |
| ______________________________________ |
| LD50 Blepharospasm |
| Narcosis potential- |
| Code (mg/kg) IP isation |
| No. IP mg/kg mg/kg T |
| ______________________________________ |
| 993 2000 200 0 200 385% |
| 994 2000 200 0 200 103% |
| 1386 1300 130 0 130 190% |
| 1292 DL0 ≧ 2000 |
| 200 0 200 62% |
| 1293 DL0 ≧ 2000 |
| 200 0 200 30% |
| 1059 DL0 ≧ 2000 |
| 200 0 200 0 |
| 1323 DL0 ≧ 2000 |
| 200 0 200 66% |
| 1325 250 25 ± 25 121% |
| 1348 100 10 ± 10 39% |
| 1350 750 75 ± 50 139% |
| 1352 150 15 0 15 0 |
| 1354 ≧2000 |
| 200 + 200 66% |
| 1274 DL0 ≧ 2000 |
| 200 ± 200 99% |
| 1266 700 70 0 70 0 |
| 1268 1000 100 ± 100 60% |
| 1270 1000 100 ± 100 .60% |
| 1040 1000 100 ++ 100 174% |
| 1446 1500 150 ± |
| 1387 100 10 0 10 40% |
| 1322 1500 150 0 150 116% |
| 1388 DL0 > 200 |
| 200 0 200 10% |
| 1324 DL0 ≧ 2000 |
| 200 0 200 83% |
| 1347 1000 100 60% |
| 1349 100 10 ± 10 10% |
| 1351 700 70 0 70 101% |
| 1353 150 15 0 15 34% |
| 1355 2000 200 0 200 49% |
| 1275 2000 200 0 200 56% |
| 1267 900 90 ± 90 .46% |
| 1269 1100 110 0 110 66% |
| 1271 500 50 0 50 0 |
| ______________________________________ |
As can be seen from the results of the pharmacological tests described above, the compounds of the invention act on the central nervous system.
They may be used in particular as adjuncts in anticomitial therapy, and as anxiolytics, anti-depressants, hypnotics and tranquilisers. Compound No. 1040 has been found to be particularly useful as an anti-depressant.
The compounds of the invention may be formulated in conjunction with a pharmaceutically compatible excipient for oral administration, for example in the form of tablets, pills or capsules, for parenteral administration in the form of solutions for injection, or for endorectal administration in the form of suppositories.
The daily dosage will be of the order of 50 to 300 mg orally and, where appropriate, 5 to to 50 mg by injection in the case of the soluble compounds.
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| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Jul 25 1978 | Unicler | (assignment on the face of the patent) | / | |||
| Jun 09 1987 | UNIVABLOT S A , | NOVAPHARME SARL, A CORP OF FRANCE | ASSIGNMENT OF ASSIGNORS INTEREST | 004766 | /0319 |
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